The proposed Program Project in Atherosclerosis represents a multidisciplinary appproach to understanding the interrelationships of blood and cell-derived factors on the sequence of pathophysiological events involved in atherogenesis. The objective of this Program is to elucidate the mechanisms involved in (1) the accumulation of cholesterol-rich plasma lipoproteins, such a LDL, in the aortic wall, (2) the formation of foam cells derived from monocyte-macrophage, and (3) the regulation of smooth muscle cell proliferation and collagen metabolism. Specifically, in Project I we will study the permeability, diffusion and degradation of LDL in the aortic wall and the relationship of these processes to LDL arterial accumulation. Projects II and III will concentrate on the fate of the blood monocyte in the aortic wall: its infiltration in response to chemotactic factors and its transformation into a foam cell. Project IV examines the stimulation of smooth muscle cell proliferation and modulation by factors derived from platelets and endothelial cells, while Project V deals with the regulation of extra- and intracellular collagen metabolism by aortic smooth muscle cells. We will use in vivo animal models (swine and rabbit) in conjunction with in vitro systems such as tissue culture to help elucidate these processes. Some specific techniques to be employed are in vivo infusion of tracers, immunochemical and histochemical techniques, in vitro radiolabeling, light and electron microscopy. These research activities will be integrated by an Administrative Core and supported by Cores in Tissue Culture and Histopathology and Electron Microscopy. The proposed program is expected to provide new and significant basic information that will lead to a clearer understanding of the initial sequence of events in atherogenesis.